The ultimate goal of this research is to achieve induction of clinical tolerance (antigen specific unresponsiveness), allowing long term survival of human organ allografts. We have shown that synthetic peptides corresponding to linear sequences of HLA molecules are potent inhibitors of the allogeneic immune response, both in vitro and in vivo. Clinical trials are in progress. The objectives of the studies proposed here are to understand the mechanism of action of the peptides, to better define the ligands involved, and to develop new therapeutic approaches using retroviral vectors. Project 1 focuses on HLA class I derived peptides, Project 2 on a newly identified class II derived peptide, and Project 3 on gene therapy approaches. These three projects are supported by an Administrative Core (A) to assure unity of purpose and quality control and a Peptide Chemistry Core (B), responsible for peptide synthesis and modification. This program builds upon established collaborations between transplant physicians, clinical scientists, basic immunologists and chemists in order to rapidly apply knowledge obtained from basic research to clinical practice. This application is designed to provide a rational basis for the application of HLA derived peptides to transplantation and autoimmune disease. Insights into the mechanism of action and ligands involved will help to design new generations of therapies aimed at the induction and maintenance of tolerance.